PROJECT SUMMARY/ABSTRACT - Project 3 Burst wave lithotripsy (BWL) is an emerging ultrasound-based technology that shows promise of being able to destroy kidney stones in the setting of a physician?s office. Project 3 will be focusing its study of BWL on the interaction of the BWL sound energy with actual human stones and with tissue. Our project is unique in its breadth of study of human patients, animal models, ex vivo kidneys, and in vitro models, all supported by mathematical modeling. In Aim 1, we will conduct in human observations of breaking stones with BWL and monitor BWL effects on renal tissue, testing the hypothesis that BWL will break stones within the human kidney without significant damage to the kidney tissue. In this Aim, Project 3 will collaborate with Project 1 to directly verify the breaking of stones by BWL within human kidneys, and simultaneously study the visible effects of BWL on tissue, with and without the addition of adaptive feedback control for cavitation. Visual documentation of stone breakage and tissue health will be done using state-of-the-art endoscopy and stone analysis techniques. In Aim 2, we will assess experimentally and theoretically the effects of tissue calcification on its interactions with BWL, testing the hypothesis that levels of calcification in tissue common to stone formers will not result in increased damage by BWL. This aim will be accomplished using in vitro test systems in which human stone material will be attached to or embedded within tissue-mimicking gels to model calcifications associated with renal papillae, and the results quantitated using micro CT imaging. All of these experiments will be done hand-in-hand with modeling by the Freund lab so that the overall results are more than simply empirical, but designed so that a deeper understanding of the mechanisms of action of BWL sound energy in tissue of stone formers will be achieved. In Aim 3, we will evaluate renal effects of BWL by measuring changes in kidney morphology and function associated with transcutaneous BWL treatment in the living pig model, testing the hypothesis that the range of treatment parameters at which BWL is both safe and highly effective can be extended using pre-treatment strategies that afford protection to kidney tissue. The pig model will be used to measure effects of BWL on renal structure and function over a range of energy doses above and below the threshold to induce ultrasound-visible cavitation linked to injury. The safety of alternating application of BWL and UP will also be tested. Protection protocols that work with SW (e.g., pretreatment with pause) will be tested for effect on renal response to BWL. In Aim 4, we will assess tissue health during BWL from acoustic emissions and a biomechanical model of tissue damage in an ex vivo perfused kidney system, testing the hypothesis that acoustic emissions from cavitation, coupled to a biomechanical tissue model can be used to monitor the health of tissue during BWL and provide real-time feedback to avoid or minimize collateral tissue injury. Passive acoustic mapping (PAM) is a technique that allows for cavitation activity to be detected and mapped in tissue in real-time. The biomechanical model employs fracture mechanics to determine how the viscoelastic properties of tissue are altered as BWL energy is deposited in the tissue.